Atypical PKC Inhibitors: A Novel Approach to Treat Retinal Diseases

Proper function of tight junctions (TJs) in the vascular endothelium of the blood-retinal barrier (BRB) is required to ensure appropriate neuronal activity. Growth factors and inflammatory cytokines, such as vascular endothelial growth factor (VEGF) and tumor necrosis factor-α (TNF-α), have been implicated in compromising TJ in the BRB. Tight junction dysfunction leads to vessel hyperpermeability and loss of neural function, which, in turn, are associated with retinal pathologies, including diabetic macular edema (DME). Although antibodies against VEGF have shown some promise in treatment of DME, research suggests that alternate therapies targeting downstream components of the VEGF pathway may be more beneficial in treatment of retinal diseases involving the BRB. Inhibition of protein kinase C-β (PKCβ), a classical PKC isoform, was an initial target for diabetic retinopathy, as VEGF’s actions through PKCβ result in TJ breaks. However, classical PKC inhibitors only partially prevented VEGF-induced BRB TJ dysfunction and permeability, and they failed to prevent TNF-α–induced permeability. Titchenell et al. recently investigated the ability of atypical PKC isoform (aPKCζ/aPKCι) inhibitors to prevent VEGF-induced TJ dysfunction. First, the laboratory demonstrated that aPKCs were activated in VEGF-injected rat retinas, and they contributed to VEGF-induced permeability in primary bovine retinal endothelial cells (BRECs). The investigators then developed novel, small molecule inhibitors of aPKC that prevented VEGF-induced permeability in vitro (BREC) and in vivo (rat retina). Studies in BREC demonstrated that aPKC inhibitors prevented VEGF-induced TJ protein disorganization, thus preventing TJ breaks in the endothelial layer. In addition, rat retinal flat mounts were prepared to determine the effect of aPKC inhibitors on the retinal vasculature TJ complex. These experiments showed that aPKC inhibitors prevented VEGF-induced disruption of occludin staining. Previous work from this laboratory demonstrated that aPKC inhibitors blocked TNF-α–induced permeability, providing evidence for the ability of these inhibitors to prevent retinal disease from both growth …